Post Traumatic Stress Disorder (PTSD) is among the most common psychiatric conditions in the population, affecting both civilians and military personnel, and is associated with significant distress and dysfunction in affected individuals. Although currently available pharmacologic treatments for PTSD are somewhat efficacious, most patients remain symptomatic after currently standard interventions;the development of novel therapeutics to treat affected individuals addresses a critical unmet clinical need. We are proposing a three-year study utilizing the R-34 mechanism to systematically assess the potential efficacy of eszopiclone for the treatment of PTSD with sleep disturbance. The study comprises a double blind, randomized, placebo controlled trial over 12 weeks of the non- benzodiazepine GABA receptor agonist eszopiclone in patients (n=40) with PTSD, and will include examination of outcomes for measures of PTSD as well as sleep, depression, and functional impairment. Further, we will assess the impact of treatment on actigraphy (as an objective measure of sleep), neuropsychological assessments of memory, and inflammatory markers (cytokines) as biomarkers of response and as part of mediator and moderator hypotheses to address questions about how this treatment may work and who might benefit from it. Addressing these aims will help inform the treatment of PTSD and have important public health significance. PUBLIC HEALTH RELEVANCE: Post Traumatic Stress Disorder (PTSD) is a common and markedly distressing and impairing condition occurring in civilian and military personnel exposed to significant traumatic stressors. Given its prevalence and morbid impact, the development of effective interventions to treat PTSD represents a critical public health need. Results of this study will provide information about the potential efficacy of a novel agent, eszopiclone, for the treatment of PTSD.